DESCRIPTION: Diabetes (DM) shortens life expectancy by about 10 years. Renal disease shows the strongest correlation with excess mortality, yet our comprehension of diabetic kidney disease (DKD) remains limited. Epigenetics refers to heritable changes in gene expression patterns that are not caused by alterations in the nucleotide sequence itself. The epigenetic system is heritable and reversible at the cellular level. Cytosine modifications fully meet these criteria. Other factors including: histone tail modifications, higher order chromatin organization and long and short non-coding RNA molecules are often described as epigenetic mechanisms, but they not fulfill all criteria as epigenetic mechanism. Several lines of evidence point to the epigenome as an important missing link in our understanding of DKD pathogenesis. The hypothesis of the proposal is that cytosine methylation changes reflect long-term prior metabolic alterations. Epigenetic differences can subgroup DKD patients and can predict kidney function decline by influencing transcript level changes. Under this proposal we plan to: 1. Characterize genome-wide cytosine methylation patterns in 800 microdissected human kidney TEC; including controls (in absence of diabetes, hypertension and normal kidney function), patients with diabetes or hypertension and absence of renal disease and patients with CKD in the setting of hypertension and compare them to DKD samples. 2. Define the contribution of cytosine methylation changes to phenotype development. Define the association between cytosine methylation and gene expression changes using novel statistical methods. 3. Understand whether cytosine methylation changes can be used to predict GFR course in the CRIC cohort, by comparing cytosine methylation changes of patients with rapidly vs. slowly progressive DKD upon enrollment.